Botulinum Neurotoxin Type A Injection Research Articles

Comparison of intradermal injection with iontophoresis of abobotulinum toxin A for the treatment of primary axillary hyperhidrosis: A randomized, controlled trial

Background: Botulinum neurotoxin type A (BTX-A) injection is the treatment of choice for idiopathic axillary hyperhidrosis (IAH) refractory to conventional treatments. Objective: This study compared the efficacy of BTX-A injection and iontophoresis for treatment of IAH in a randomized controlled trial. Methods: In eleven patients with the diagnosis of IAH, one axilla was randomly treated with injections of 1.5 mL (250 MU) of BTX-A, and the other side was treated with BTX-A administered by iontophoresis. The amount of sweating, skin hydration, transepidermal water loss, pain, and patient satisfaction on both axilla were compared with baseline levels, and also between both sides 1 week, 1 month, and 6 months after treatment. Results: The injection side had significantly less sweat production than the iontophoresis side 1 week, 1 month, and 6 months after treatment (84%, 76%, and 50% vs. 73%, 22%, and 32%, respectively). The response to iontophoresis was more stable than that to injection. Participants' pain perception during the procedure score was significantly less on the iontophoresis side compared with the injection side (15.0 vs. 20.0, p < 0.05). Conclusion: This study has shown that injection is a more effective method for the administration of BTX-A, though iontophoresis can also be considered a non-invasive and painless method in some patients.

Botulinum neurotoxin type A injection of the pelvic floor muscle in pain due to spasticity: a review of the current literature

The role of muscle spasm is not a new concept in the genesis of pain. Botulinum neurotoxin type A (BoNTA) has been successfully employed in a variety of muscular and inflammatory conditions. The aim of our study was to review the published literature on the role of BoNTA injection of the pelvic floor muscle in the management of women with chronic pelvic pain (CPP). A systematic search of the literature published up to June 2012 on the use of BoNTA in the treatment of female pelvic floor muscle spasm was carried out using relevant search terms in MEDLINE and EMBASE databases. The results were limited to full-text English language articles. Relevant trials as well as relevant reviews were selected and analyzed by two independent reviewers. Five studies (2 case reports, 1 prospective pilot study, 1 retrospective study and 1 randomised double-blind placebo controlled study) were included in this systematic review. Overall, BoNTA has shown to be beneficial in relieving CPP related to pelvic floor spasm. The role of BoNTA as a treatment of CPP has been recognized for more than 10 years. Although data are still scarce preliminary results are encouraging. BoNTA is an attractive option for refractory CPP related to pelvic floor muscle spasm, but further studies using validated and reproducible outcome measures are needed, to establish its effectiveness, safeness, technique, optimal dosage, and duration of symptom relief.

Current Aesthetic Use of AbobotulinumtoxinA in Clinical Practice: An Evidence-Based Consensus Review

The amount and complexity of scientific and clinical evidence for aesthetic use of botulinum neurotoxin type A (BoNT-A) has expanded rapidly in recent years, especially for abobotulinumtoxinA, necessitating reassessment of current knowledge about aesthetic use of abobotulinumtoxinA and other BoNT-A preparations. A committee of 13 plastic surgeons, facial plastic surgeons, and dermatologists engaged in a live discussion of information from a systematic literature review and an Internet-based survey of their beliefs and practices. The committee achieved consensus on most issues. It was concluded that doses of different BoNT-A preparations cannot be interconverted with a fixed ratio. The size of the "field of effect" is difficult to measure, and comparisons between preparations have yielded equivocal results. Nonresponse due to neutralizing antibodies appears exceedingly rare with currently available BoNT-A preparations and of little concern clinically. BoNT-A dose, injection depth, and injection technique should be adjusted according to the anatomic area being treated and each patient's individual characteristics and goals. Aesthetic use of BoNT-A has a good safety profile. Most adverse events are minor and related to the trauma of injection, although special care is needed in certain anatomic areas. Detailed recommendations for treatment of different anatomic areas are presented. BoNT-A products are often used in conjunction with other treatment modalities (eg, fillers and resurfacing), but little agreement was reached on best practices. The findings reported in this consensus document may serve as a practical guide for aesthetic practitioners as they apply the latest knowledge about BoNT-A in providing their patients with optimal care.

Reduction of TRPV1 expression in the trigeminal system by botulinum neurotoxin type-A

Botulinum neurotoxin type-A (BoNT-A) is clinically used for patients with pain disorders and dystonia. The precise mechanism whereby BoNT-A controls pain remains elusive. Here, we studied how BoNT-A affects the expression of the transient receptor potential vanilloid subfamily member 1 (TRPV1), a cation channel critically implicated in nociception, in the trigeminal system. Histological studies revealed that subcutaneous BoNT-A injection (0.25, 0.5, or 5ng/kg) into the face targeted the ophthalmic division of trigeminal ganglion (TG) neurons and decreased TRPV1-immunoreactive neurons in the TG and TRPV1-immunoreactive fibers in rat trigeminal terminals. Of note, TG neurons that received projections from the dura mater, a principal site of headache generation, had reduced TRPV1 expression. BoNT-A-induced cleavage of SNAP25 (synaptosomal-associated protein of 25-kDa) in the TG became obvious 2days after BoNT-A administration and persisted for at least 14days. Quantitative real-time RT-PCR (reverse transcription-polymerase chain reaction) data indicated that the TRPV1-decreasing effects of BoNT-A were not mediated by transcriptional downregulation. By employing a surface protein biotin-labeling assay, we demonstrated that BoNT-A inhibited TRPV1 trafficking to the plasma membrane in primary TG neurons. Moreover, Y200F-mutated TRPV1, which is incapable of trafficking to the plasma membrane, was expressed in PC12 cells by transfection, and pharmacological studies revealed that TRPV1 in the cytoplasm was more predisposed to proteasome-mediated proteolysis than plasma membrane-located TRPV1. We conclude that the mechanism by which BoNT-A reduces TRPV1 expression involves the inhibition of TRPV1 plasma membrane trafficking and proteasome-mediated degradation in the cytoplasm. This paradigm seems to explain how BoNT-A alleviates TRPV1-mediated pain. Our data reveal a likely molecular mechanism whereby BoNT-A treatment reduces TRPV1 expression in the trigeminal system and provide important clues to novel therapeutic measures for ameliorating craniofacial pain.

Botulinum Toxin-A–Induced Protective Ptosis in the Treatment of Lagophthalmos Associated With Facial Paralysis

To evaluate the safety and efficacy of the protective ptosis created by botulinum neurotoxin type-A in lagophthalmos cases due to peripheral facial paralysis. Protective ptosis was induced by 7.5 U botulinum neurotoxin type-A injection into levator muscles in 15 patients with peripheral facial paralysis and lagophthalmos. Its efficacy and safety were evaluated prospectively. Complete ophthalmological examinations were performed before and after injections; interpalpebral fissure, upper eyelid margin reflex distance, and levator muscle function were measured. In control visits, degree and duration of ptosis and side effects of the drug were evaluated. The mean age of the patients was 55 ± 14.28 years (22-78 years). Ptosis created by botulinum neurotoxin type-A injection was severe in 12 patients (80%), moderate in 2 patients (13.3%), and mild in 1 patient (6.7%). The effect of botulinum neurotoxin type-A began in 2.33 ± 1.44 days and peaked in 5.73 ± 2.63 days. No patient needed a second injection. The mean duration for ptosis was 10.53 ± 2.89 weeks. After development of ptosis, statistically significant improvement in corneal symptoms (p < 0.01) and decrease in daily artificial tear requirement (p < 0.01) were detected. Local or systemic side effects were not observed in any of the patients. In patients with peripheral facial paralysis and lagophthalmos, protective ptosis created by botulinum neurotoxin type-A injection into the levator muscle is a reliable and effective technique for the protection of the ocular surface and treatment of existing corneal complications. It represents an alternative treatment modality in cases requiring surgery.

Botulinum Neurotoxin Type A for the Treatment of Benign Prostatic Hyperplasia: Randomized Study Comparing Two Doses

Purpose. To assess the efficacy and safety of intraprostatic injection of two botulinum neurotoxin type A (BoNT-A) doses for the treatment of benign prostatic hyperplasia (BPH). Materials and Methods. Men with symptomatic BPH who failed medical treatment were randomized to receive 100 U or 200 U of BoNT-A into the prostate. The International Prostatic Symptom Score (IPSS), maximum flow rate (Qmax), post-void residual volume (PVR), PSA levels and prostate volume before injection and after 3 and 6 months were evaluated. Adverse events were compared between the groups. Results. Thirty four patients were evaluated, including 17 in the BoNT-A 100 U group and 17 in the BoNT-A 200 U group. Baseline characteristics were similar in both groups. Both doses produced significant improvements in IPSS, Qmax and PVR after 3 and 6 months and both doses promoted comparable effects. Prostate volume was affected by 200 U BoNT-A injection only after 6 months of treatment. PSA levels were significantly affected in the 100 U group only after 6 months of treatment. In the 200 U group, PSA levels were significantly decreased after 3 and 6 months. The complication rate was similar in both groups. Conclusions. Efficacy and safety of both BoNT-A doses are similar for BPH treatment in the short term followup.

Botulinum toxin has an increased effect when targeted toward the muscle’s endplate zone: A high-density surface EMG guided study

Objectives To compare the effect of endplate-targeted injections of a low Botulinum neurotoxin type A (BoNT-A) dose with that of injections at defined distances from the motor endplate zone. Methods In eight healthy volunteers, the main endplate zones of the right and left extensor digitorum brevis (EDB) muscles were localized using high-density surface EMG. On the study side BoNT-A was injected at fixed distances from the endplate zone. On the control side, BoNT-A was administered into the endplate zone. Compound muscle action potential (CMAP) prior to the injection and 2, 12, and 24 weeks later were recorded. Results On the control side, the mean CMAP reduction 2 weeks after BoNT-A injection was 79.3%. The difference in CMAP reduction between both EDB muscles was significantly related to the injection distance from the endplate zone. Increasing the injection distance by 1 cm reduced the effect of BoNT-A by 46%. Conclusions Guided injection of a reduced BoNT-A dose into the muscle’s endplate zone(s) is a promising strategy for optimizing the therapeutic effectiveness of BoNT-A and for minimizing side-effects such as unwanted weakness of adjacent muscles. Significance Precise endplate-targeted injections increase the effect of BoNT-A and may thus prove to reduce required dosage and treatment costs.

Botulinum neurotoxin type A (BoNTA) decreases the mechanical sensitivity of nociceptors and inhibits neurogenic vasodilation in a craniofacial muscle targeted for migraine prophylaxis

The mechanism by which intramuscular injection of BoNTA into the craniofacial muscles decreases migraine headaches is not known. In a blinded study, the effect of BoNTA on the mechanical and chemical responsiveness of individual temporalis muscle nociceptors and muscle neurogenic vasodilation was investigated in female rats. Mechanical threshold was measured for 3h following intramuscular injection of BoNTA or vehicle, and for 10min after a subsequent injection of the algogen glutamate. Injection of BoNTA significantly increased the mechanical threshold of muscle nociceptors without altering the muscle surface temperature and blocked glutamate-induced mechanical sensitization and neurogenic vasodilation. None of these effects were reproduced by pancuronium-induced muscle paralysis. Western blot analysis of temporalis muscles indicated that BoNTA significantly decreased SNAP-25. Measurement of interstitial glutamate concentration with a glutamate biosensor indicated that BoNTA significantly reduced glutamate concentrations. The mechanical sensitivity of muscle nociceptors is modulated by glutamate concentration through activation of peripheral NMDA receptors. Immunohistochemical experiments were conducted and they indicated that half of the NMDA-expressing temporalis nerve fibers co-expressed substance P or CGRP. Additional electrophysiology experiments examined the effect of antagonists for NMDA, CGRP and NK1 receptors on glutamate-induced effects. Glutamate-induced mechanical sensitization was only blocked by the NMDA receptor antagonist, but muscle neurogenic vasodilation was attenuated by NMDA or CGRP receptor antagonists. These data suggest that injection of BoNTA into craniofacial muscles acts to decrease migraine headaches by rapidly decreasing the mechanical sensitivity of temporalis muscle nociceptors through inhibition of glutamate release and by attenuating the provoked release of CGRP from muscle nociceptors.

Botulinum toxin assessment, intervention and after‐care for lower limb spasticity in children with cerebral palsy: international consensus statement

Botulinum neurotoxin type-A (BoNT-A) has been used in association with other interventions in the management of spasticity in children with cerebral palsy (CP) for almost two decades. This consensus statement is based on an extensive review of the literature by an invited international committee. The use of BoNT-A in the lower limbs of children with spasticity caused by CP is reported using the American Academy of Neurology Classification of Evidence for therapeutic intervention. Randomized clinical trials have been grouped into five areas of management, and the outcomes are presented as treatment recommendations. The assessment of children with CP and evaluation of outcomes following injection of BoNT-A are complex, and therefore, a range of measures and the involvement of a multidisciplinary team is recommended. The committee concludes that injection of BoNT-A in children with CP is generally safe although systemic adverse events may occur, especially in children with more physical limitations (GMFCS V). The recommended dose levels are intermediate between previous consensus statements. The committee further concludes that injection of BoNT-A is effective in the management of lower limb spasticity in children with CP, and when combined with physiotherapy and the use of orthoses, these interventions may improve gait and goal attainment.

Botulinum toxin assessment, intervention and aftercare for paediatric and adult drooling: international consensus statement

Many individuals with neurological problems or anatomical abnormalities of the jaw, lips or oral cavity may drool, which can impact on health and quality of life. A thorough evaluation of the patient's history, examination of the oral region by a speech pathologist and, in individuals over 3 years, a dental examination is warranted. Questionnaires with established validity such as the Drooling Impact Scale are useful assessment tools. A hierarchical approach to treatment is taken from least invasive therapies, such as speech pathology, to more invasive, such as injection of botulinum neurotoxin type-A (BoNT-A) into the salivary glands (parotid and submandibular). The wishes of the individual and their carer are crucial considerations in determining the suitability of the intervention for the patient. In the presence of dysphagia and cerebral palsy (CP), careful assessment is required prior to the injection of BoNT-A. Favourable responses to intervention include a reduction in the secretion of saliva and in drooling, as well as psychosocial improvements. BoNT-A is usually well tolerated, although potential side effects should be discussed with the patient and carer.

Botulinum toxin versus submandibular duct relocation for severe drooling

Botulinum neurotoxin type A (BoNT-A) has been described as an effective intervention for drooling and is being increasingly adopted. However, its effectiveness compared with established treatments is still unknown. We undertook a within-participants observational study to examine this. An historic cohort was formed of 19 children and young adults (10 males, nine females) with severe drooling who underwent BoNT-A injections followed by surgical re-routing of the submandibular duct at least 6 months later. Mean age at time of admission was 11 years 5 months (range 5-17 y) and mean age at the time of surgery was 14 years (range 6-23 y). Fifteen children were diagnosed with bilateral cerebral palsy (CP), three with unilateral CP, and one with non-progressive developmental delay. Gross Motor Function Classification System levels were the following: level I, n=1; level II, n=2; level III, n=7; level IV, n=6; and level V, n=3). The primary outcome was the drooling quotient, which was assessed before each intervention and 8 and 32 weeks thereafter. A multivariate analysis of variance of repeated measures was performed, with the measurement points as the within-participant variables. The drooling quotient was reduced to a greater extent after surgery than after BoNT-A administration (p=0.001). Compared with a baseline value of 28, the mean drooling quotient 8 weeks after surgery was 10, and 32 weeks after surgery was 4 (p<0.001). Among the group treated with BoNT-A, the drooling quotient showed a significant reduction from a baseline value of 30 to 18 after 8 weeks (p=0.02), and a continued but diminished effect after 32 weeks (drooling quotient 22; p=0.05). Both interventions are effective, but surgery provides a larger and longer-lasting effect.

Botulinum toxin and urinary bladder disorders in women: new insight into an old problem

The overactive bladder (OAB) and painful bladder (bladder pain syndrome/interstitial cystitis) syndromes are common urological problems that frequently co-exist and severely affect the quality of life of many women. As yet, the pathophysiology of both conditions is incompletely understood, and therefore the results of available treatment including drug therapy are usually disappointing. Botulinum neurotoxin type A (BoNT-A) is increasingly used in humans for pharmaceutical and cosmetic purposes. The toxin is produced from fermentation of the bacterium Clostridium botulinum. Due to ease of administration and relatively long-lasting effects, BoNT-A is now widely used in clinical practice amongst several medical specialties, particularly in dermatology and plastic surgery mainly for cosmeceutical rejuvenation [1]. More recently, there is abundant literature supporting the use of BoNT-A in urology and urogynecology, and the off-label use of this drug continues to grow in both disciplines worldwide. Although the first use of BoNT-A in lower urinary tract disorders was reported 22 years ago [2], evidence-based information to guide current urogynecologic practice is still lacking. BoNT-A has unique physio-pharmacological properties that includes a muscle-paralyzing effect via inhibition of acetyl-choline release from motor nerves into the neuromuscular junction. This induces temporary chemodenervation that produces relaxation of both skeletal and smooth muscles. Another potentially very important property of BoNT-A is the ability to inhibit afferent neurotransmission inhibition. This leads to a very potent analgesic effect by inhibition of ATP secretion, reduced production of substance P, and reduced axonal expression of capsaicin, purinergic receptors, and nerve growth factors [3]. The therapeutic rationale for using BoNT-A in lower urinary tract disorders in women is primarily based on both the muscle relaxant and analgesic actions. Anticholinergic agents are the mainstay of pharmacologic treatment of OAB because of the ability to reduce bladder contractions and associated symptoms in most patients. These drugs are, however, associated with poor tolerability and relatively poor patients’ compliance because of the high incidence of anticholinergic adverse effects such as dry mouth, blurred vision, and constipation. In fact, almost 17% of participants withdrew from clinical trials of anticholinergic drugs because of this reason alone [4]. Over the past two decades, the use of cystoscopic intra-detrusor injection of BoNT-A has revolutionized the treatment of OAB, particularly the intractable symptoms associated with neurogenic OAB induced by spinal cord lesions and diseases [5]. Challenging cases of neurogenic OAB that are often associated with poor control of symptoms on standard E. Kocjancic (*) Department of Urology, College of Medicine, University of Illinois at Chicago, 840 S Wood Street, Chicago, IL 60612, USA e-mail: ekocjanc@uic.edu

International consensus recommendations on the aesthetic usage of botulinum toxin type A (Speywood Unit) – part I: upper facial wrinkles

Azzalure (Galderma SA) is a newly approved European botulinum neurotoxin type A (BoNT-A). It is derived from Dysport (Ipsen Pharma), which has a long history of usages in various applications. Azzalure and Dysport are collectively referred to as BoNT-A (Speywood Unit) and are different from other BoNT-A preparations. To provide consensus recommendations on the treatment of upper face wrinkles with BoNT-A (Speywood Unit). The members of the International Board on Botulinum toxin Azzalure (IBBA) convened to develop consensus on the treatment of upper facial wrinkles based on their own extensive experience. The consensus recommendations address the general issues regarding treatment and provide specific guidelines on the anatomy, injection points, dose, injection technique and safety precautions concerning each common upper face indication. The recommended final concentration of BoNT-A (Speywood Unit) is 200 s.U/mL (10 s.U/0.05 mL) after reconstitution. For glabellar lines, the members recommend a total of five injection points with 10 s.U/point. For forehead wrinkles, the members recommend four to six injections into the frontalis with 5-10 s.U/point. For crow's feet, the members recommend three injections per side with 5-10 s.U/point at the lateral part of the orbicularis oculi. For lateral eyebrow lift, the members recommend one point at each eyebrow tail and an additional one in each side of the frontalis with 5-10 s.U/point. This guideline provides a framework for physicians who wish to perform safe and efficacious injection of BoNT-A (Speywood Unit).

The Science and Manufacturing Behind Botulinum Neurotoxin Type A-ABO in Clinical Use

Since the first comprehensive description of the physiologic effects of botulism toxicity in the 1820s, specific formulations of botulinum neurotoxin type A (BoNT-A) have been developed. Now, a new botulinum neurotoxin type A formulation (BoNTA-ABO; Dysport [abobotulinumtoxinA]; Medicis Aesthetics, Scottsdale, AZ) has been made available in the United States and these same physiologic effects have become beneficial clinical targets. This formulation has been used successfully for nearly 20 years in Europe and other countries under the trade name Dysport (Clostridium botulinum type A toxin-hemagglutinin complex; Ipsen Biopharm, Wrexham, UK). BoNT-A injections are administered to achieve temporary local flaccid paralysis of targeted muscles. Injection of BoNT-A formulations for aesthetic purposes was by far the most common minimally-invasive (nonsurgical) cosmetic procedure performed in the United States in 2008. The objective of this review is to describe the latest data regarding the mechanism of action of BoNTA-ABO, the potential roles of neurotoxin-associated proteins (NAP), the manufacturing standards for these biologic products, and the specific manufacturing process and characteristics of BoNTA-ABO. A systematic search using the US National Library of Medicine PubMed database was performed and the relevant articles were reviewed. Direct input and data from the worldwide manufacturer of Dysport have been included. The four sequential steps in the mechanism of action of BoNTA-ABO are binding, internalization, translocation, and intracellular proteolysis of the target protein. Although all BoNT-A products must meet standards for quality, potency, and safety, they should not be considered equivalent formulations because they have different production strains of the bacterium C botulinum, as well as different isolation and manufacturing processes that result in unique product characteristics. The production steps for Dysport-including a unique proprietary purification process using column chromatography and a unique proprietary finishing process-result in consistent and unique product features. Studies confirm that Dysport has a high degree of long-term batch-to-batch consistency for a range of specified properties, including specific potency, protein composition, toxin complex charge-density properties, and endopeptidase activity. In the native, natural form, NAP protect the endogenous neurotoxin from degradation in the acidic environment of the stomach; in biologic formulations, they may have effects on the structural stability, binding, uptake, and transcytosis of BoNT-A products in other areas of the body. NAP are most likely to stabilize the neurotoxin in a vial of clinical product. A thorough understanding of the mechanism of action, product characteristics, and effects of NAP is important to ensure appropriate and safe clinical use of BoNT-A products. Now approved in the United States, Dysport is an important addition to the group of available BoNT-A formulations.

In the Human Urothelium and Suburothelium, Intradetrusor Botulinum Neurotoxin Type A Does Not Induce Apoptosis: Preliminary Results

BackgroundIntradetrusor injections of botulinum neurotoxin type A (BoNTA) are emerging as the preferred second-line treatment for neurogenic and idiopathic overactive bladder (OAB). In animal experiments, intradetrusor BoNTA injections have been shown to cause apoptosis in the bladder urothelium and suburothelium but not the detrusor. ObjectiveTo investigate BoNTA-induced apoptosis in patients with refractory neurogenic OAB. Design, setting, and participantsTwelve refractory OAB patients with neurogenic detrusor overactivity resulting from multiple sclerosis (MS) and seven controls were included prospectively. MeasurementsThe number of apoptotic cells before and 4 wk after first intradetrusor BoNTA (300 U of BOTOX [Allergan, Irvine, CA, USA]) injections were estimated using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) staining. Results and limitationsComparison of TUNEL-positive cells (yes vs no) in the bladder urothelium and suburothelium revealed no significant differences in OAB patients before (4 of 12, 33%) versus after (3 of 12, 25%) BoNTA treatment (p=0.99). In addition, no significant differences (p=0.99) were found in OAB patients versus controls. Because our findings are based on first intradetrusor BoNTA injections only, it is unclear whether the results could be extrapolated to repeat injections. ConclusionsIn contrast to preliminary animal experiments, first intradetrusor BoNTA injections for treating refractory neurogenic OAB—a highly effective treatment—did not induce apoptosis in the bladder urothelium and suburothelium.

Botulinum Toxin Dilution and Endplate Targeting in Spasticity: A Double-Blind Controlled Study

Gracies J-M, Lugassy M, Weisz DJ, Vecchio M, Flanagan S, Simpson DM. Botulinum toxin dilution and endplate targeting in spasticity: a double-blind controlled study. Objective To determine the effects of botulinum neurotoxin type A (BTX-A) dilution and endplate-targeting in spastic elbow flexors. Design Double blind randomized controlled trial; 4-month follow-up after a 160-unit injection of BTX-A into spastic biceps brachii (4 sites). Randomization into: group 1: 100 mouse units (MU)/mL dilution, 0.4cc/site, 4-quadrant injection; group 2: 100MU/mL dilution, 0.4cc/site, 4 sites along endplate band; group 3: 20MU/mL dilution, 2cc/site, 4-quadrant injection (n=7 per group). Setting Institutional tertiary care ambulatory clinic. Participants Referred sample of 21 adults with spastic hemiparesis. No participant withdrew due to adverse effects. Intervention A 160-unit injection of BTX-A of different dilutions and locations into biceps brachii. Main Outcome Measures Primary: agonist and antagonist (cocontraction) mean rectified voltage (MRV) of elbow flexors/extensors during maximal isometric flexion/extension; secondary: maximal voluntary power of elbow flexion/extension; spasticity angle and grade in elbow flexors/extensors (Tardieu Scale); active range of elbow extension/flexion. Results BTX-A injection overall reduced agonist flexor MRV (–47.5%, P<0.0001), antagonist flexor MRV (–12%, P=.037), antagonist extensor MRV (–19%, P<.01), flexion maximal voluntary power (–33%, P<.001), elbow flexor spasticity angle (–30%, P<.001) and grade (–17%, P=.03), and increased extension maximal voluntary power (24%, P=.037) and active range of elbow extension (5.5%, 8°, P=.002). Agonist and antagonist flexor MRV reductions in group 3 (–81% and –31%) were greater than in groups 1 and 2, whereas increase in active range of elbow extension was greater in group 2 (10%) than in groups 1 and 3 ( P<.05, analysis of covariance [ANCOVA]). Elbow flexor spasticity was significantly reduced in groups 2 and 3 only ( P<.05, ANCOVA). Conclusions In spastic biceps, high-volume or endplate-targeted BTX-A injections achieve greater neuromuscular blockade, cocontraction and spasticity reduction, and active range of elbow extension improvement, than low volume, nontargeted injections.

Suburothelial Myofibroblasts in the Human Overactive Bladder and the Effect of Botulinum Neurotoxin Type A Treatment

BackgroundAn increasing body of evidence suggests a possible role of suburothelial myofibroblasts (MFs) in bladder mechanosensation and in the pathophysiology of detrusor overactivity (DO). ObjectiveTo determine whether markers of MFs, including gap junction protein connexin43 (Cx43) and c-kit have altered immunohistochemical expression in the suburothelium of patients with neurogenic DO (NDO) or idiopathic DO (IDO) and whether this is affected by successful treatment of DO with botulinum neurotoxin type A (BoNTA). Design, setting, and participantsPatients with NDO (n=10) or IDO (n=11) were treated in a single-centre, open-label study of intradetrusor BoNTA injections. Control tissue was obtained from 10 patients undergoing pelvic-floor repair procedures who had no overactive bladder (OAB) symptoms. This study is registered with ClinicalTrials.gov, number NCT00662064. InterventionsBladder biopsies performed with flexible cystoscopes were obtained from control subjects and from NDO and IDO patients before BoNTA treatment and at 4 wk and 16 wk after treatment. They were studied with quantitative immunofluorescence using antibodies to connexin 43 (Cx43), vimentin, and c-kit. MeasurementsDifferences in Cx43, vimentin, and c-kit immunoreactivity between control subjects and NDO or IDO patients (primary outcomes). Changes in NDO or IDO, Cx43 immunoreactivity, and c-kit immunoreactivity after BoNTA treatment (secondary outcomes). Results and limitationsCx43 immunoreactivity was increased in both IDO and NDO patients compared to controls, but remained unchanged after BoNTA treatment. C-kit immunoreactivity was similar in NDO/IDO patients and controls and remained unchanged after BoNTA treatment. ConclusionsIncreased gap junction formation in the suburothelium has been demonstrated in biopsies from humans with DO. It is hypothesised that this change could have a significant role in the pathogenesis of the detrusor abnormality. Successful treatment of NDO or IDO does not appear to be associated with changes in the expression of Cx43 or c-kit on suburothelial MFs.

Mechanisms of Prostate Atrophy after Glandular Botulinum Neurotoxin Type A Injection: An Experimental Study in the Rat

BackgroundPrevious studies in humans, dogs, and rats have shown that intraprostatic injection of botulinum neurotoxin type A (BoNTA) reduces gland size. ObjectiveTo investigate the role of eventual impairment of sympathetic, parasympathetic, and sensory nerves to gland atrophy after intraprostatic BoNTA administration. Design, setting, and participantsAdult male Wistar rats weighing 300–350g were used. InterventionAnimals were injected in the prostate ventral lobes with 0.2ml of saline (n=6) or the same volume containing 10U BoNTA (BOTOX) (n=18). Six rats treated with BoNTA further received the adrenergic agent phenylephrine (PHE, 0.05mg/kg per day), six received the cholinergic drug bethanechol (2mg/kg per day), and six received subcutaneous saline. Animals were sacrificed 1 wk later. MeasurementsProstates were weighed, fixed, and stained for sympathetic (tyrosine hydroxylase [TH]), parasympathetic (vesicular acetylcholine [ACh] transporter [VAChT]), and sensory nerve (calcitonin gene-related peptide [CGRP]) visualisation. Terminal deoxynucleotidyl transferase biotin-dUTP nick-end labelling (TUNEL) reaction was performed to investigate apoptosis. Results and limitationsProstate weight in controls was 1.82±0.24mg/100g of rat weight. In BoNTA-treated rats, weight decreased to 1.28±0.18mg /100g of rat weight (p=0.002). In BoNTA plus PHE–treated rats, prostate weight was similar to controls: 1.78±0.27 (p=0.87). In rats treated with BoNTA plus bethanechol, weight was less than controls: 1.41±0.17 (p=0.01). The number of TH-positive fibres was markedly reduced after BoNTA (p<0.001). VAChT- and CGRP-positive fibres were scarce in controls, preventing further evaluation. Rats treated with BoNTA had more TUNEL-positive cells than controls (p<0.001) and rats treated with BoNTA plus PHE (p<0.001). There were no differences between the BoNTA and BoNTA plus bethanechol groups (p=0.81).Although showing atrophy after BoNTA injection, rat prostates do not develop benign prostatic hyperplasia (BPH). Thus, present findings should be used cautiously to explain prostate atrophy seen in men with BPH treated with BoNTA. ConclusionsProstate atrophy induced by BoNTA in the rat may be the result of sympathetic nerve impairment and decreased adrenergic stimulation of the gland. Data indirectly suggest that sympathetic drive plays a role in prostate-size regulation.

Botulinum neurotoxin type A injections reduce spasticity in mild to moderate hereditary spastic paraplegia— Report of 19 cases

Hereditary spastic paraplegia (HSP) is characterized by lower extremity spasticity. Symptomatic therapy generally includes physical therapy and oral antispastic agents, in selected cases intrathecal baclofen. Because of the positive results in other treatments of spasticity, the use of botulinum neurotoxin type A (BoNT-A) might also be considered for patients with HSP. We report the effect of BoNT-A injections in 19 unselected patients with HSP treated by the members of the German Spasticity Education Group. In 17 patients, the modified Ashworth scale had improved by one point. In one patient, it improved by three points. Most of the patients reported reduction of spasticity. BoNT-A injections were continued in 11 of 19 patients (57.9%). All of the patients with continued injections had a good or very good global subjective improvement. Patients with less pronounced spasticity and patients with accompanying physical therapy tended to exhibit a better effect. Only four patients reported adverse effects which were increased weakness in three patients and pain in one patient. BoNT-A injections appear to reduce spasticity effectively and safely, especially in patients with mild to moderate spasticity. The preliminary results of our case series should encourage larger studies of BoNT-A injections in HSP.

The Analgesic Effect of Botulinum-toxin A on Postwhiplash Neck Pain

The effectiveness of botulinum neurotoxin type A (BTXA) injections in relieving the neck pain and reduced motion that evolve after whiplash injury (WI) has been controversial. To test the long-term efficacy of a tender point injection of BTXA in relieving neck pain in patients with WI. Twenty patients with cervical myofascial pain, 2 to 48 weeks after WI, were randomly assigned to receive either 200 U of BTXA or placebo at 4 tender points and were seen during the follow-ups 3, 6, 9, 12, and 24 weeks after the injections. Outcome measures included the intensity of pain as evaluated by a 10-cm Visual Analog Scale (VAS) and a 5-point Verbal Rating Scale (VRS), quality of life as evaluated by the SF-36 questionnaire, treatment efficacy as per the global assessment of the physician and patient, intensity of pain in response to mechanical pressure, range of cervical motion, and use of other therapies and their adverse effects. A time-dependent improvement in all the parameters was found in both groups, which was consistently larger in the BTXA-treated group, but mostly not at a significant level. Significant differences between the groups were found only in the percentages of patients who achieved 50% or more of reduction in intensity (VAS and average VRS) at 24 weeks (50% vs. 0%, P>0.05 and 70% vs. 11%, P>0.05, respectively). Systemic adverse effects tended to be more common in the BTXA-treated group (40% vs. 0%, P=0.07). Study results suggest that BTXA treatment has some efficacy when administered within 1 year of the WI. However, a large, well-designed clinical trial is needed to draw final conclusions.